Diabetes最新文献

{"title":"Body Composition–Driven Phenotyping Reveals Obesity and Cardiometabolic Heterogeneity in Children Using a Tree-Like Representation","authors":"Pei Xiao, Hong Cheng, Jingfan Xiong, Yinkun Yan, Junting Liu, Li Liu, Hongbo Dong, Yan Li, Peiyu Ye, Liwan Fu, Liwang Gao, Fangfang Chen, Xinying Shan, Lina Lan, Yanyan Li, Jie Mi","doi":"10.2337/db26-0136","DOIUrl":"https://doi.org/10.2337/db26-0136","url":null,"abstract":"Traditional measures such as BMI do not fully capture obesity-related metabolic risks. Here, we examined DXA-derived body composition patterns in children (n = 11,238) using the discriminative dimensionality reduction tree algorithm, which was validated in an independent cohort (n = 2,001). The tree structure revealed a continuous landscape of body composition phenotypes, with distinct spatial gradients for fat and lean mass. Within the phenotypic tree, fat-dominant phenotypes clustered in the region of low dimension 1 and low dimension 2 (corresponding to the lower left branches), where they demonstrated significant spatial overlap with high-risk clusters for hypertension, elevated LDL cholesterol (LDL-C), total cholesterol, and triglycerides (TG) (Moran I >0.3, all P < 0.001). Meanwhile, phenotypes characterized by elevated lean mass coupled with increased adiposity were localized in the region of low dimension 1 and high dimension 2 (upper left branches), demonstrating an increased risk of low HDL-C and high TG (Moran I >0.6, all P < 0.001). In contrast, lean-dominant phenotypes clustered in the region of high dimension 1 and high dimension 2 (upper right branches), which were associated with a relatively low risk of hyperglycemia, insulin resistance, and high LDL-C (Moran I >0.1, all P < 0.001). For practical utility, we developed a publicly available web application to map individual data on the reference tree architecture, allowing for assessment of cardiometabolic risk. Our findings highlight the value of more precise body composition measures for early identification and prevention of obesity-related health problems. Article Highlights Childhood obesity shows large differences in body composition and health risk that are not well captured by BMI or simple metabolic classifications, prompting the need for more precise characterization. This study aimed to determine whether a data-driven framework integrating detailed body composition measures could better describe obesity-related phenotypic heterogeneity and its relationship with cardiometabolic risk in children. We delineated a continuous body composition manifold encompassing fat-dominant, lean-dominant, and concomitant high-mass phenotypes, which captured diverging cardiometabolic risk trajectories and yielded modest incremental improvements in risk prediction. These findings support more precise risk stratification and provide a practical tool to improve early identification and prevention of obesity-related health complications in children.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"67 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Loss-of-Function ZNRF3 Mutation Impairs Adipose Thermogenesis and Drives Subcutaneous Fat Expansion","authors":"Ningning Zhang, Peng Lu, Yangyi Tong, Zhiwen Cao, Yinmeng Zhu, Yujia Gong, Nan Yin, Ruikai Yang, Muye Tong, Na Chen, Yuxiao Zhao, Chao Wu, Qian Li, Zhongyun Zhang, Xinyuan Zhou, Dongqin Gu, Yansong Liu, Qianyun Cheng, Zhiguo Zhang, Jieli Lu, Yufang Bi, Yong Geng, Weiqing Wang, Guang Ning, Jie Hong, Weiqiong Gu, Ruixin Liu, Jiqiu Wang","doi":"10.2337/db25-1108","DOIUrl":"https://doi.org/10.2337/db25-1108","url":null,"abstract":"Zinc and ring finger protein 3 (ZNRF3) functions as a transmembrane E3 ubiquitin ligase. Although genome-wide association studies have implicated ZNRF3 in body fat distribution, the evidence from human genetics and animal models has been lacking. Here, through whole-exome sequencing of 1,944 obese individuals and 2,161 healthy lean control individuals, we identified a rare loss-of-function mutation in human ZNRF3 (p.V228L) observed exclusively in 8 obese individuals. These carriers exhibit increased hip circumference and subcutaneous fat area and lower fasting glucose levels compared with noncarriers. In mice, adipocyte-specific Znrf3 deletion leads to progressive adiposity, with expansion of subcutaneous white adipose tissue (sWAT) and improved glucose tolerance after a long-term high-fat diet. Furthermore, Znrf3 deficiency impairs the browning capacity of sWAT and cold-induced thermogenesis. A knock-in mouse model harboring the homologous human p.V228L mutation recapitulates key features of carriers and knockout mice, including reduced sWAT thermogenic function, altered fat distribution, and improved glucose tolerance. Mechanistically, Znrf3 loss attenuates the cAMP/cAMP-dependent protein kinase signaling pathway, suppressing UCP1 expression and mitochondrial respiration. Collectively, these findings provide genetic and biological evidence that ZNRF3 regulates thermogenic capacity and remodeling of sWAT, offering new insights into obesity heterogeneity. Article Highlights A rare loss-of-function variant in ZNRF3 (p.V228L) is enriched in individuals with obesity and is associated with increased subcutaneous white adipose tissue (sWAT) accumulation and lower fasting glucose levels. Both adipocyte-specific Znrf3 knockout and global variant knock-in impair sWAT browning, increase sWAT expansion, and improve glucose tolerance in mice. These findings establish ZNRF3 as a genetic regulator of fat distribution and thermogenic capacity, informing precise phenotyping of obesity. GWAS has implicated ZNRF3 in human fat distribution, yet its role in adipose tissue biology remains unknown.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"337 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomics-Defined Subtypes of Prediabetes and Risk of Cardiovascular-Kidney-Metabolic Outcomes","authors":"Fei Chen, Yang Zhang, Weihao Wang, Ge Li, Jian Zhang, Peiheng Zhang, Jingcui Guo, Wuxiang Xie, Feifei Zhang, Ying Gao","doi":"10.2337/db26-0218","DOIUrl":"https://doi.org/10.2337/db26-0218","url":null,"abstract":"Prediabetes is highly prevalent and biologically heterogeneous, yet current glycemic definitions do not adequately capture differences in cardiometabolic and kidney risk. We aimed to identify metabolically defined subtypes of prediabetes using circulating metabolites and to examine their associations with cardiovascular-kidney-metabolic outcomes. We analyzed 24,638 participants with prediabetes from the UK Biobank who had metabolomics data available. Metabolomic biomarkers related to type 2 diabetes, cardiovascular disease, and chronic kidney disease were identified using machine learning–based feature selection methods, and unsupervised clustering was applied to derive metabolic subtypes. Associations between subtypes and cardiometabolic outcomes were evaluated, and interactions between dietary patterns and metabolic subtypes were explored. Mendelian randomization analyses were conducted to investigate potential causal roles of key metabolomic biomarkers. Three metabolically distinct subtypes of prediabetes were identified, representing low-, intermediate-, and high-risk metabolic profiles. These subtypes showed progressively higher risks of developing type 2 diabetes, cardiovascular disease, and chronic kidney disease during follow-up, and the associations between diet quality and disease outcomes differed across subtypes. Several metabolomic biomarkers demonstrated potential causal links with cardiometabolic outcomes. These findings highlight the metabolic heterogeneity of prediabetes and suggest that metabolomics-based subtypes may improve risk stratification and support precision prevention strategies. Article Highlights Previous studies have identified heterogeneity among prediabetes subgroups using clinical characteristics; however, biological and metabolic heterogeneity remains insufficiently captured. This study examined whether data-driven clustering based on metabolomic biomarkers could define distinct prediabetes subtypes with differential type 2 diabetes, cardiovascular disease, and chronic kidney disease risk. Using 16 metabolomic biomarkers, we identify three metabolically distinct clusters showing progressively higher risks of incident type 2 diabetes, cardiovascular disease, and chronic kidney disease. Differential diet-cluster associations across clusters were obtained, and Mendelian randomization supported potential causal roles for several metabolomic biomarkers. Metabolomics-based stratification may improve risk prevention and enable cluster-specific dietary interventions in prediabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"26 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148703417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular Regenerative Cell Flux in Diabetes: Mechanistic and Clinical Implications","authors":"Fallon Dennis, Cole J. Dennis, Adrian Quan, Hwee Teoh, Francesco Cosentino, Subodh Verma, David A. Hess","doi":"10.2337/db26-0372","DOIUrl":"https://doi.org/10.2337/db26-0372","url":null,"abstract":"Type 2 diabetes mellitus (T2DM) disrupts the quantity, phenotype, and function of circulating vascular regenerative (VR) progenitor cells that are critical to vessel repair. These impairments include reduced progenitor clonogenicity, mobilization and homing to areas of ischemia, and imbalances in secretory function, collectively contributing to poor vascular healing and complications such as peripheral artery disease, critical limb ischemia, and cardiovascular disease. Despite growing recognition of VR cell exhaustion, regenerative strategies remain hindered by imprecise cell phenotyping, underused functional assays, and insufficient integration of disease-relevant in vivo models. This article examines the evolving landscape for the integrated assessment of function, encompassing multipotent colony-forming cell assays, single-cell RNA sequencing, advanced proteomic and metabolomic profiling, and novel models to evaluate vessel regeneration through human cell transplantation into immune-deficient mice with T2DM-associated comorbidities. We also highlight promising regenerative strategies using glucose-reducing agents, alongside rigorous omics-driven precision profiling to quantify the recovery of VR cell function during T2DM, underscoring an urgent need to progress beyond phenotypic studies toward functionally integrated models that predict translational efficacy. Article Highlights Vascular regenerative cells, including endothelial precursor cells and hematopoietic progenitor cells, exhibit altered regenerative function in type 2 diabetes. Traditional definitions of endothelial precursor cells lack phenotypic specificity, limiting interpretation of regenerative capacity across studies. Functional assays, including colony formation, migration, and in vivo ischemic models for type 2 diabetes, have revealed defects in angiogenesis, proliferation, and repair. Emerging omics approaches provide mechanistic insight into vascular regenerative cell exhaustion across metabolic and inflammatory states. Standardized phenotyping and functional assays are needed to improve the translational success of regenerative therapies for cardiometabolic diseases.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"8 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148703416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Selective Cullin 3 RING E3 Ligase Inhibitor Attenuates Hyperglycemia via Dual Insulin Sensitizing and Insulinotropic Action","authors":"Lijie Gu, Lei Xiong, Mohammad Nazmul Hasan, Yanhong Du, Timothy Wu, Tiangang Li","doi":"10.2337/db26-0029","DOIUrl":"https://doi.org/10.2337/db26-0029","url":null,"abstract":"Hyperglycemia is a hallmark of type 2 diabetes and a key pathogenic driver of diabetes complications. Cullin RING E3 ligases (CRLs) are multisubunit E3 ubiquitin ligases that mediate cellular protein turnover. The activity of CRLs requires cullin neddylation, a posttranslational modification that can be pharmacologically targeted with therapeutic potentials. By using hyperinsulinemic euglycemic clamp analysis, we discover that pan-neddylation inhibitor exerts both an insulin sensitization effect in liver and muscle and an insulinotropic effect in pancreatic β-cells. This dual action is mediated by cullin 3 (Cul3), a member of the seven canonical cullin family proteins. DI-1859, a selective Cul3 neddylation inhibitor, effectively protects against hyperglycemia in obese mice. DI-1859 enhances insulin signaling by preventing Cul3-mediated insulin receptor substrate degradation in liver and muscle cells. DI-1859 increases insulin secretion in a glucagon-like peptide-1–independent manner in mice and directly enhances insulin secretion in INS-1 832/13 β-cells and human islets. Cul3 inhibition leads to Ras homolog family member A (RhoA) stabilization. RhoA regulation of cytoskeleton remodeling may play a role in mediating the insulinotropic effect of DI-1859 in β-cells. In conclusion, this study demonstrates that a single agent targeting Cul3 neddylation promotes peripheral insulin sensitization and β-cell insulin secretion to attenuate hyperglycemia in mice. Article Highlights Pan-neddylation inhibitors exhibit potent hypoglycemic effect. The target organs and mechanisms underlying the hypoglycemia effect of pan-neddylation inhibitors are incompletely understood. We found that inhibition of cullin 3 leads to a dual insulin sensitization and insulinotropic effect. Selective inhibition of cullin 3 neddylation is a feasible approach to lower hyperglycemia.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"68 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148633862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid-Specific Heparanase Aggravates Insulitis in Type 1 Diabetes via Heparan Sulfate Fragment-Dependent Amplification of Macrophage Polarization","authors":"Jia Zhang, Meiwei Li, Xiaohang Zhou, Hailing Ni, Yiyue Huang, Xin Hu, Huangmo Lin, Xinyuan Cao, Xiao Han, Peng Sun","doi":"10.2337/db26-0365","DOIUrl":"https://doi.org/10.2337/db26-0365","url":null,"abstract":"The intraislet heparan sulfate (HS) barrier is essential for β-cell survival, yet its role in type 1 diabetes (T1D) remains incompletely understood. We investigated the expression pattern, pathogenic function, and therapeutic potential of the heparanase (HPSE)-HS axis in T1D by integrating single-cell RNA sequencing data sets from human and mouse islets and peripheral immune cells, together with genetic mouse models and pharmacological intervention. HPSE was selectively enriched in myeloid cells, particularly CD14++ classical monocytes from patients with T1D and NOD mice and was associated with activated proinflammatory and interferon signaling. In diabetic islets, increased HPSE expression was accompanied by marked degradation of the HS barrier. Myeloid-specific Hpse deficiency improved glucose tolerance, enhanced insulin secretion, and reduced infiltration of inducible nitric oxide synthase–positive macrophages and T cells, whereas islet-specific Hpse overexpression accelerated autoimmune diabetes and insulitis. Mechanistically, HPSE-mediated HS cleavage generated bioactive fragments that acted as costimulatory signals, amplifying IFN-γ–STAT1 signaling and promoting M1 macrophage polarization. Pharmacological inhibition of HPSE with muparfostat preserved the intraislet HS barrier and improved glucose homeostasis in nonobese T1D models. Collectively, these findings identify myeloid-derived HPSE as a key driver of T1D pathogenesis through dual effects on HS barrier disruption and inflammatory amplification and establish the HPSE-HS axis as an important regulator of the islet inflammatory microenvironment and a promising adjuvant therapeutic target for T1D. Article Highlights The role of the heparanase (HPSE)–heparan sulfate (HS) axis in type 1 diabetes remains incompletely defined. We examined whether myeloid-derived HPSE drives islet inflammation, how HS fragments influence macrophage polarization, and whether pharmacological inhibition is protective. We found that myeloid HPSE disrupts the intraislet HS barrier and that the resulting HS fragments potentiate interferon-γ–STAT1 signaling to promote proinflammatory macrophage polarization. Genetic or pharmacological inhibition of HPSE preserved islet integrity and ameliorated diabetes, identifying this pathway as a potential therapeutic target in type 1 diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"47 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148633863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual Modulation of Prostaglandin E2 Receptors EP3 and EP4 Protects β-Cell Mass in a Model of Aggressive Autoimmune Inflammation","authors":"Juliann B. Burkett, Jennifer Fuhr, Alexander C. Falk, Prasanna Dadi, Alexa N. Del Bene, Audrey Lucerne, Dudley McNitt, Landon M. Clark, Micaela Maxwell, Victoria Gaeth, Kaelyn Allen, David Jacobson, Daniel J. Moore, Christopher S. Wilson, Maureen Gannon","doi":"10.2337/db25-1007","DOIUrl":"https://doi.org/10.2337/db25-1007","url":null,"abstract":"Type 1 diabetes is driven by both β-cell dysfunction and an autoreactive immune system, resulting in β-cell destruction and hyperglycemia. We previously showed that pharmacological modulation of prostaglandin E2 (PGE2) receptor (EP) signaling protects β-cells from cytokine-mediated death ex vivo, and relieves oxidative stress and maintains β-cell identity in a mouse model of type 2 diabetes. Here we show that EP modulation protects against cytokine-mediated β-cell death in islets from nonobese diabetic (NOD) mice. Because PGE2 can also alter immune cell phenotypes, we tested whether EP modulation prevents β-cell destruction in a setting of aggressive autoimmunity in vivo. Simultaneous blockade of the inhibitory EP3 receptor and activation of the stimulatory EP4 receptor delayed onset of hyperglycemia, prevented loss of β-cell mass, and reduced insulitis in cyclophosphamide-treated female NOD mice. Despite reduced insulitis, there were no changes in several systemic T-cell populations, including regulatory T cells. However, EP modulation altered islet cytokine expression and, within β-cells, preserved identity, sustained activation of the antioxidant factor NRF2, and reduced evidence of senescence. Thus, the PGE2 signaling pathway is a potential target for protecting β-cell mass under aggressive autoimmune attack to treat or prevent type 1 diabetes. Article Highlights Modulation of prostaglandin E2 (PGE2) signaling improves β-cell health and survival. In this study, we examined whether these β-cell effects could be harnessed alongside known PGE2-mediated immunomodulation to ameliorate β-cell loss in a model of severe islet autoimmunity. Simultaneous pharmacological blockade of the EP3 receptor and activation of the EP4 receptor maintain mature β-cell mass, ameliorate the proinflammatory insulitic microenvironment, and alter β-cell stress responses in female nonobese diabetic mice undergoing aggressive inflammatory assault. EP modulation shows promise to support β-cell resiliency and reduce inflammation in a setting of autoimmune attack, such as type 1 diabetes.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"85 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148633763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Fat-Muscle Patterns Drive Sex-Specific Diabetes Risk: UK Biobank Evidence","authors":"Yifan Ma, Ning Zhou, Boya Yu, Zixiao Liang, Mengjie Xiao, Guoqiang Jing, Xu Zhang, Xin Liu, Changhao Sun, Huanyu Wu","doi":"10.2337/db26-0096","DOIUrl":"https://doi.org/10.2337/db26-0096","url":null,"abstract":"This study aimed to identify integrated body composition patterns and evaluate their sex-specific associations with incident type 2 diabetes (T2D). Among 258,500 UK Biobank participants free of diabetes at baseline, principal component analysis (PCA) was applied to 28 anthropometric, fat, lean, bone, and muscle strength traits. Cox models assessed associations with incident T2D, and least absolute shrinkage and selection operator (LASSO)-penalized Cox and weighted quantile sum (WQS) regression identified key components. During a mean follow-up of 11 years, 33,636 incident T2D cases were identified. PCA yielded seven interpretable patterns. LASSO consistently identified generalized adiposity, leg-dominant lean distribution, and central leanness as robust components across sexes. Compared with the low-score reference group, generalized adiposity was associated with higher T2D risk in men and women (hazard ratio [HR] 1.73 [95% CI 1.33–2.24] and 2.21 [1.55–3.16], respectively), whereas leg-dominant lean distribution was associated with lower risk (HR 0.57 [0.48–0.68] and 0.50 [0.40–0.63]). Central leanness was associated with lower risk in women (HR 0.41 [0.34–0.51]) and showed a nonmonotonic association with risk in men. In WQS analyses, central leanness contributed more strongly to the inverse mixture association in men, whereas leg-dominant lean distribution contributed more strongly in women. These findings highlight sex-specific fat-lean configurations in diabetes risk. Article Highlights Conventional obesity measures do not capture the multidimensional nature of body composition or the integrated distribution of fat and lean tissue. We aimed to identify integrated body composition patterns and determine their sex-specific associations with incident type 2 diabetes risk. We identified distinct composite body composition patterns associated with diabetes risk in men and women, with generalized adiposity linked to higher risk and leg-dominant lean distribution or central leanness linked to lower risk. These findings suggest that multidimensional fat-muscle patterns provide complementary information beyond conventional obesity measures for understanding diabetes risk.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"101-B 10 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148461859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Frequency Feeding With Late-Night Snacking Accelerates Type 2 Diabetes and Alters Diurnal Metabolic Gene Expression in Male KKAy Mice","authors":"Ning Ma, Yang Xue, Yuxing Tang, Hongxia He, Shanqiang Xu, Xiaohui Yang, Rong Song, Qianqian Yang, Kai Li, Yu Zhao, Huizhen Cai","doi":"10.2337/db25-0845","DOIUrl":"https://doi.org/10.2337/db25-0845","url":null,"abstract":"We investigated whether sustained high-frequency feeding (six meals per day) increases type 2 diabetes mellitus (T2DM) incidence and alters diurnal metabolic patterns in male KKAy mice. Mice were randomly assigned to three or six isocaloric meals per day for 60 days. Metabolic phenotyping, tissue glycogen assays, multitissue circadian clock gene analysis, and exploratory correlation analyses of gene coexpression were performed. Our results demonstrated that high-frequency feeding significantly increased body weight, fasting glucose levels, and T2DM incidence (relative risk = 2.1) compared with three-meal feeding. Six-meal feeding exhibited larger diurnal glucose/insulin oscillations, earlier and higher hepatic glycogen accumulation, disrupted muscle glycogen rhythmicity, and elevated expression of hepatic metabolic genes. Exploratory correlation analyses revealed altered diurnal coexpression patterns among clock and metabolic genes, although causal or regulatory inferences are not warranted from mRNA-level data alone. These findings support meal frequency as an independent modulator of metabolic health and provide preclinical evidence relevant to chrononutrition strategies for T2DM prevention. Article Highlights Meal frequency as an independent determinant of type 2 diabetes mellitus (T2DM) risk under strictly isocaloric conditions remains undefined. We investigated whether increasing meal frequency from three to six isocaloric meals per day alters T2DM incidence and diurnal metabolic and gene expression patterns in male KKAy mice. High-frequency feeding with late-night snacking significantly increased T2DM incidence (relative risk = 2.1), disrupted diurnal glucose and insulin rhythms, increased hepatic glycogen accumulation, and elevated hepatic metabolic gene expression, with altered diurnal coexpression patterns. These findings establish meal frequency as an independent modifier of metabolic health and provide preclinical evidence supporting chrononutrition-based strategies for T2DM prevention.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"31 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148459908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Acting RXR Agonism Preserves Retinal Function and Modulates Inflammation in Diabetic Retinopathy","authors":"Emory Johnson, Ehsan Kaffash, Fadeela Sheini, Ashley Rennhack, Micheli Severo Sielski, Assylbek Zhylkibayev, Sergio L.I. Calzi, Sagun Poudel, Venkatram Atigadda, Qingguo Xu, Maria B. Grant, Marina S. Gorbatyuk","doi":"10.2337/db26-0053","DOIUrl":"https://doi.org/10.2337/db26-0053","url":null,"abstract":"Diabetic retinopathy (DR) is a leading cause of vision loss and is associated with reduced nuclear retinoid X receptor (RXR) activity. Retinal explants exposed to high glucose showed downregulation of RXR, peroxisome proliferator–activated receptor (PPAR), and liver X receptor-β and their lipid metabolism targets (Abca1, Scd1, and Acox1). Supplementation with the RXR agonist UAB126 restored nuclear receptor signaling and preferentially activated RXR/PPAR heterodimers. We evaluated UAB126 microparticles (UAB126-MP), a sustained-release RXR agonist formulation, for pharmacokinetic, molecular, and functional effects in db/db mouse retinas. A single intravitreal injection of UAB126-MP provided extended drug exposure for up to 6 months and increased retinal RXRα expression. Functionally, UAB126-MP preserved scotopic and photopic electroretinographic responses at 2 months and sustained cone photoreceptor function at 6 months. However, it did not reduce acellular capillaries. At 6 months, immunostaining and flow cytometry revealed decreased retinal macrophage/microglial infiltration and reduced CD45-positive myeloid cells and monocytes. These findings indicate that RXR agonism supports neuronal protection and immune modulation but does not prevent vasodegeneration, suggesting primarily neuroprotective and anti-inflammatory actions. Collectively, UAB126-MP confers durable retinal protection through nuclear receptor–mediated pathways, underscoring its potential as a long-acting therapeutic strategy for DR. Article Highlights High glucose exposure of retinal explants reduces expression of nuclear receptors retinoid X receptor (RXR), peroxisome proliferator–activated receptor, and liver X receptor-β, and treatment with UAB126 increases the formation of RXR-peroxisome proliferator–activated receptor heterodimers. Sustained release of UAB126-loaded microparticles enables intravitreal drug delivery for up to 6 months. Intravitreal UAB126 microparticles injection in diabetic mice confers long-term neuroprotection and anti-inflammatory benefits. RXR-targeted therapy represents a promising approach strategy for managing diabetic retinopathy.","PeriodicalId":11376,"journal":{"name":"Diabetes","volume":"13 1","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148461860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}